SH2-B Promotes Insulin Receptor Substrate 1 (IRS1)- and IRS2-mediated Activation of the Phosphatidylinositol 3-Kinase Pathway in Response to Leptin

Duan, Chaojun; Li, Minghua; Rui, Liangyou

doi:10.1074/jbc.m408495200

Cited by 145 publications

(129 citation statements)

References 49 publications

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“…This association may be attributable, however, to the effects of the polymorphism on the neuroendocrine systems, given that neuroendocrine disorders can result in a decrease in the concentration of growth hormone and sex steroids and thus accelerate the development of osteoporosis (24). SH2B1 is a widely-expressed cytoplasmic protein that simultaneously binds, via its Src homology 2 (SH2) domain, to both Janus kinase 2 (JAK2) and insulin receptor substrate 2 (IRS2), thereby promoting the leptin-induced activation of the phosphoinositide 3-kinase signaling pathway in cultured cells (25,26). SH2B1-deficient mice develop insulin resistance and type 2 diabetes mellitus (27) as well as severe leptin resistance, hyperphagia and obesity (28).…”

Section: Discussionmentioning

confidence: 99%

Association of genetic variants of MAOA and SH2B1 with bone mineral density in community-dwelling Japanese women

Yamada

Ando²,

Shimokata³

2008

Mol Med Report

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Abstract. Although bone mineral density (BMD) is a complex trait that is influenced by both genetic and environmental factors, heritability studies in twins and families have shown that genetic factors account for 60-85% of its variance. We examined the relation of the variable number of tandem repeats (VNTR) polymorphism of the monoamine oxidase A gene (MAOA) and the A'G (Thr484Ala) polymorphism of the SH2B adaptor protein 1 gene (SH2B1) to BMD in communitydwelling Japanese women and men. The 2235 subjects (1107 women, 1128 men) were aged 40-79 years and were randomly recruited for a population-based prospective cohort study of aging and age-related diseases in Japan. BMD at the distal and proximal radius was measured by peripheral quantitative computed tomography, and the BMD of the total body, lumbar spine (L2-L4), right femoral neck and right trochanter was measured by dual-energy X-ray absorptiometry. The genotypes of the VNTR polymorphism of MAOA were determined by DNA fragment analysis, and those of the A'G (Thr484Ala) polymorphism of SH2B1 by melting curve analysis. The VNTR polymorphism of MAOA was associated with the BMD of the distal radius, total body, lumbar spine and trochanter in all women, and with the BMD of the total body and trochanter in postmenopausal ones, with the L (four repeats) and S (two or three repeats) alleles reflecting increased and decreased BMD, respectively. The A'G (Thr484Ala) polymorphism of SH2B1 was associated with the BMD of the lumbar spine in all women, with the BMD of the proximal radius in premenopausal women and with the BMD of the lumbar spine, femoral neck and trochanter in postmenopausal women, with the variant G allele being related to increased BMD. These results suggest that MAOA and SH2B1 are determinative loci for bone mass in Japanese women, especially in postmenopausal ones.

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Section: Discussionmentioning

confidence: 99%

Association of genetic variants of MAOA and SH2B1 with bone mineral density in community-dwelling Japanese women

Yamada

Ando²,

Shimokata³

2008

Mol Med Report

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“…Among those, SH2B1 encodes a Src homology adaptor protein involved in leptin and insulin signaling. 25,26 Common variants near this locus are associated with BMI, serum leptin, and body fat in genome-wide association studies (GWASs), [27][28][29][30] while rare dominant mutations have been reported to cause obesity, social isolation, aggressive behavior, and speech and language delay. 31 None of the CNV-contained genes have been associated with ASD or HC defects.…”

Section: Introductionmentioning

confidence: 99%

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Loviglio

Arbogast

Jønch³

et al. 2017

The American Journal of Human Genetics

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Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

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“…SH2B1 C-terminal SH2 domain binds to phosphoTyr 813 in JAK2 as discussed above; in contrast, its N-terminal region binds to different sites on JAK2 in a tyrosine phosphorylation-independent manner [43] . Similarly, SH2B1 binds to phospho-tyrosine(s) of IRS1 or IRS2 via its SH2 domain, and binds to other sites on IRS proteins via its PH domain-containing regions in a tyrosine phosphorylation-independent fashion [46] . SH2B1 forms homodimers or oligomers via its N-terminal domains [15][16][17] .…”

Section: Sh2b1 Mediates/modulates Leptin Signalingmentioning

confidence: 99%

“…Genetic deletion of IRS2 in LEPR-expressing cells results in leptin resistance and obesity in mice [45] . SH2B1 directly binds to both IRS1 and IRS2 in addition to JAK2 [46] . In response to leptin, SH2B1 recruits IRS proteins to JAK2, thus allowing JAK2 to phosphorylate IRS proteins on tyrosine residues [46] .…”

Section: Sh2b1 Mediates/modulates Leptin Signalingmentioning

confidence: 99%

“…SH2B1 directly binds to both IRS1 and IRS2 in addition to JAK2 [46] . In response to leptin, SH2B1 recruits IRS proteins to JAK2, thus allowing JAK2 to phosphorylate IRS proteins on tyrosine residues [46] . Accordingly, in SH2B1 knockout mice, leptin is unable to stimulate tyrosine phosphorylation of hypothalamic IRS2 [10] .…”

Section: Sh2b1 Mediates/modulates Leptin Signalingmentioning

confidence: 99%

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SH2B1 regulation of energy balance, body weight, and glucose metabolism

Rui

2014

WJD

Self Cite

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The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo-or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IRS2. SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/ IRS1/2 signaling complex. SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins. Accordingly, genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, and type 2 diabetes in mice. Neuronspecific overexpression of SH2B1β transgenes protects against diet-induced obesity and insulin resistance. SH2B1 in pancreatic β cells promotes β cell expansion and insulin secretion to counteract insulin resistance in obesity. Moreover, numerous SH2B1 mutations are genetically linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Unlike SH2B1, SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis. The metabolic function of the SH2B family is conserved from insects to humans. Key words: Obesity; Type 2 diabetes; Leptin resistance; Insulin resistance; Glucose intolerance; Hypothalamus; Energy balance; Food intake; Hyperphagia; Nonalcoholic fatty liver disease Core tip: The Src homology 2B (SH2B) family members mediate cell signaling in response to a variety of hormones, cytokines, and growth factors. In the brain, SH2B1 enhances leptin signaling and leptin's antiobesity action. In peripheral tissues, SH2B1 cell-autonomously enhances insulin signaling. In pancreatic islets, SH2B1 is required for compensatory β cell expansion in response to insulin resistance and β cell stress. SH2B1-deficiency results in severe leptin resistance, energy imbalance, obesity, and type 2 diabetes. SH2B1 mutations are linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Thus, SH2B1 is a critical metabolic regulator in mammals.Rui L. SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes 2014; 5(4): 511-526 Available from:

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SH2-B Promotes Insulin Receptor Substrate 1 (IRS1)- and IRS2-mediated Activation of the Phosphatidylinositol 3-Kinase Pathway in Response to Leptin

Cited by 145 publications

References 49 publications

Association of genetic variants of MAOA and SH2B1 with bone mineral density in community-dwelling Japanese women

Association of genetic variants of MAOA and SH2B1 with bone mineral density in community-dwelling Japanese women

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

SH2B1 regulation of energy balance, body weight, and glucose metabolism

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